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Uterine leiomyosarcoma (ULMS) is a malignancy, which arises from the uterine smooth muscle. Because of its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, PTEN knockout, KRAS mutant (PTEN KO/KRAS) mice. ULMS quickly developed in SB PTEN KO/KRAS mice, but not in PTEN KO/KRAS mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of ZFP217, was shown to be elevated in human ULMS compared with paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, whereas overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 ( NRDC in humans), showed stronger expression in human metastatic tumors compared with primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, whereas overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. SIGNIFICANCE: An in vivo Sleeping Beauty transposon mutagenesis screen identifies candidate cancer genes that drive initiation and progression of uterine leiomyosarcoma and may serve as therapeutic targets., (©2021 American Association for Cancer Research.)

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

We report a case of peripheral primitive neuroectodermal tumor (pPNET), which belongs to the pPNET/Ewing's sarcoma family, arising in the chest wall of a 69-year-old man. He had high levels of serum neuron-specific enolase and pro-gastrin-releasing peptide, which are believed to be useful diagnostic blood markers for small cell lung carcinoma (SCLC). Microscopically, the tumor was composed of solid nests and sheets of monotous, primitive, small round cells with a few rosettes, making it difficult to distinguish from SCLC. Immunohistochemically, the tumor cells showed intense cell membranous immunoreactivity for MIC2 protein (CD99). EWS/FLI-1 chimeric mRNA that originated from the characteristic t(11;22)(q24;q12) chromosomal translocation was detected by RT-PCR and nucleotide sequence analysis. These results confirmed the diagnostic validity of the present tumor being a pPNET, thus raising the possibility that in the past, pPNETs which have arisen in the chest have been mistakenly diagnosed as SCLC.

Seventy-eight patients with resected carcinoma of the lung classified as T1 and which arose in the periphery of the lung during the past 10 years were reviewed in order to evaluate both diagnostic methods in assessment of lung cancer and surgical survival. According to the size of the surgically excised lung tumor measured in greatest diameter, the patients were divided into Groups A, B, C and D. From the diagnostic point of view, procedures performed to establish a conclusive diagnosis during surgery, so-called exploratory thoracotomy, were most prevalent in Groups A, B, and C and least in Group D in decreasing degree. On the contrary, the frequency with which diagnosis could be achieved preoperatively increases with size of tumor. Metastases to the regional lymph nodes were found in Group D at a greater rate than in the other 3 groups. However there was no statistical correlation between histologic types and metastases to regional lymph nodes. The 5-year survival rate was 66.7% in Group A, 72.7% in Group B, 21.2% in Group C and 35.4% in Group D. And there was a statistically significant difference between Groups A and B and Groups C and D.

Twenty-six patients with histologically confirmed large cell carcinoma of the lung were evaluated. The overall five-year survival of these cases was 19.9%. Fifteen patients who had undergone surgical resection, excluding one operative death, had a five-year survival rate of 33.8%. None of the nonresected cases survived more than six months after the beginning of treatment. Among prognostic factors in surgical treatment of large cell carcinoma, survival correlated well with clinical stage, extent of lymph-node metastasis, curative resection and histological subtypes. As for histological subtypes, stratified subtype by division of nongiant cell carcinoma revealed poorer prognosis than that of nonstratified subtype and appeared to have some correlation with the frequency of vascular invasion by the tumor. From the clinical viewpoint, giant cell carcinoma should be regarded as a distinct clinical entity. Two cases, however, had benefit of long-term survival due to surgical modality. The clinicopathological analysis of those cases remains to be resolved in the future.

When proteins in the tissue extracts of lung cancers were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (PAGE), a 37,000-dalton protein (37K) was detected as a prominent form in all cases thus far examined. This protein was barely detectable or its amount was very small in the normal lung tissue extracts. Two-dimensional PAGE of lung tumor extracts showed 37K as a major spot with an isoelectric point of 7.6. An antibody against 37K was raised in a rabbit by injecting purified 37K. Immunoblot analysis of normal lung and lung tumor tissues revealed that the affinity-purified anti-37K antibody specifically recognized 37K and that the intensities of immunostaining corresponded to those of Coomassie brilliant blue staining.

This is a case report of a 19-year old woman with primary leiomyosarcoma of the lung. The tumor was successfully diagnosed by the bronchial brushing method under fluoroscopic guidance. Cellular features of the leiomyosarcoma are described in detail.

5 patients with histologically and/or cytologically confirmed lung cancer were treated with Cis-platinum (CDDP) infused into the bronchial artery (BAI). 2 patients with squamous cell carcinoma disclosed hypervascular type and 3 patients with adenocarcinoma demonstrated avascular or hypovascular type on bronchial arterial angiography. All patients showed more than 20% shrinkage of the tumor shadow on chest X-ray taken 2 weeks after BAI and were evaluated to be radiologically effective by Takeuchi's criteria. One patient with squamous cell carcinoma who underwent lobectomy after BAI with 100 mg of CDDP showed grade III histological effects by Shimosato's criteria. The other patient had superior vena cava syndrome and showed regression of a tumor which occluded the orifice of the right upper and showed lobe after BAI with 100 mg of CDDP. By of contrast, only 1 out of the 3 patients with adenocarcinoma who under went resection showed a grade IIa histological effect after BAI with 50 mg of CDDP. Side effects included mild gastrointestinal toxicity in 1 out of the 5 patients. In conclusion, BAI with CDDP was shown to be sufficiently useful as a chemotherapeutic modality for lung cancer, especially for patients with squamous cell carcinoma, because higher local doses can be delivered without systemic toxicity.

In a study of 65 of patients with bronchogenic carcinoma who had thoracotomy over a 5-year period, cytodiagnosis by 3-day consecutive sputum cytology was reported positive for malignant cells in 55.4%. Data analysis revealed that the overall cytodiagnosis correlated with clinical stage, tumor size, site of origin, topography and histologic types. From the histologic standpoint, the site of origin was significantly related to the positive cytology in patients with squamous cell carcinoma among factors influencing the results of sputum cytology. On the other hand, there was a correlation of tumor size and the positive cytology in patients with adenocarcinoma. In addition, poor prognosis related to the positive cytology in adenocarcinoma cases in terms of the relationship between the results through sputum examination and survival. The authors emphasized that sputum cytology has proven to be a valuable factor for determining prognosis, especially in patients with adenocarcinoma.

A case of a 55-year-old female patient with an oncocytic variety of carcinoid tumor of the lung is reported. Electron microscopic observation of marked hyperplasia and increase in number of mitochondria in the tumor cells suggested it to be of oncocytic variety and membrane bound electron dense granules were characteristically found in the tumor cells which were histologically diagnosed as carcinoid.

On the basis of prognosis in conjunction with tumor behavior, 22 patients with pulmonary metastatic osteosarcoma who had a systematic with combination of surgery and adjuvant chemotherapy were compared with thirteen patients treated randomly in the initial period. The thirteen patients had median survival of 5 months with median tumor-free interval of 6 months. Six of the twenty two patients, however, are alive and 16 had median survival of 15 months with median tumor-free interval of 14 months. In 20 of the twenty two treated with repeated or bilateral thoracotomies, there was a correlation between decrease number of metastatic lesions with number of thoracotomies and survival. Wedge excision performed repeatedly produced only minimal loss of vital capacity, compared with lobectomy. Dn bloc resection of pericardium, chest wall, and diaphragm enhanced no survival. The patients with tumor-free interval of greater than 8 months survived or succumbed to the disease and was associated with mitotic ratio of more than 10 or less. Both of chest X-ray and CT scan had a positive diagnostic rate of 41% and 67%, respectively. Currently, we conclude that modified Thomfold 's indication is applicable to the patient with pulmonary metastatic osteosarcoma with bilateral or multiple nodules and more than 8 months of tumor-free interval.

We have shown that a Mr 37,000 protein whose expression is strongly enhanced in human lung cancer tissues is the subunit of glyceraldehyde-3-phosphate (GAPDH, EC 1.2.1.12). We have isolated a GAPDH complementary DNA from human lung cancer cells and deduced the complete amino acid sequence of the encoded protein. The structure of the lung cancer GAPDH is identical to that of liver GAPDH. In addition, we have found that GAPDH mRNA expression is markedly increased in human lung cancer tissues. These results disclose a molecular basis of increased glycolysis in cancer cells and reveal an important role of energy creating reaction in cancer cell growth.

Ten patients with histologically and/or cytologically confirmed lung cancer were treated with cis-platinum (CDDP) infused into the bronchial artery (BAI). Radiological findings on chest X-rays taken two weeks after BAI were evaluated according to Takeuchi's criteria. The radiological results were judged to be quite effective in one case of squamous cell carcinoma, with more than 50% shrinkage of the tumor shadow, and to be effective in nine others, with more than 20% shrinkage. As for the histological effects, grade III in one case of squamous cell carcinoma and grade IIa in two cases of adenocarcinoma and one of large cell carcinoma were obtained by Shimosato's criteria. In conclusion, BAI with CDDP was sufficiently useful as a chemotherapeutic modality for lung cancer, especially squamous cell carcinoma, because higher local dosage of CDDP can be delivered without systemic toxicity.

We review our results with fast neutron therapy in Pancoast's tumor, and compare them with results obtained by photon beam therapy. 13 patients with Pancoast's tumor were divided into two groups; Group I (8 patients) received fast neutron therapy. Group II (5 patients) were treated by voltage X-ray therapy. 1. Group I was comprised of 3 patients receiving mixed beam therapy (TDF 80-100) and 5 patients subjected to boost therapy. All group II patients received 3100 to 8000 rads. 2. Fast neutron therapy was effective in 7 patients. In group II, high voltage X-ray therapy was effective in only 3 patients. 3. Two group I patients are still alive without signs of recurrence. The others died with a mean survival of 11 months. All group II patients died; their mean survival was 4.2 months. Our results suggest that fast neutron therapy is suitable and effective in patients with Pancoast's tumor.